The present invention relates to a process for the coupling of a) carbon monoxide together with water, ammonia, alcohols or primary or secondary amines or b) nucleophiles selected from the group of alcohols, thioles, amines, metallised hydrocarbons, CH-acidic compounds and metal cyanides, to organic compounds selected from the group of leaving-group-containing aromatics, hetero-aromatics with a C-bonded leaving group, aromatic or hetero-aromatic methyl compounds with a leaving group bonded to the methyl group, ethylenically unsaturated organic compounds with a C-bonded leaving group, or organic allyl compounds with a leaving group in allyl position, or c) vinyl compounds with leaving-group-containing aromatics, in the presence of Pd-phosphine complexes with ligands from the group of secondary aliphatic monophosphines as catalyst, and optionally in the presence of an inorganic base or organic nitrogen base; the use of Pd-phosphine complexes with secondary aliphatic monophosphines as catalysts for these coupling reactions; new Pd-phosphine complexes; and a composition comprising (a) a Pd(II) salt, a Pd(II) complex salt or a Pd(0) complex and (b) a secondary monophosphine.
It has been known for a long time that Pd-phosphine complexes catalyse the coupling of vinyl compounds, of carbon monoxide mixed with water, ammonia, alcohols or amines, or of nucleophiles, to aromatics, whilst cleaving a leaving group. An overview of this reaction is given in J. Tsuji, Palladium Reagents and Catalysts, John Wiley and Sons, 1996). The phosphine lidands used are primarily tertiary phosphines or ditertiary diphosphines, which are stable in the air and therefore easier to handle. The nucleophile-substituted aromatics are thereby obtainable in good yields and in reasonable reaction times, especially if tertiary phosphines with two to three sterically demanding alkyl groups are used as ligands (see for example A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 1998, 37, 3387ff). The preparation of such tertiary phosphines is complex and expensive.
It has now surprisingly been found that for the coupling reaction the secondary monophosphines with sterically demanding aliphatic substituents, which are significantly simpler to produce and are partly available commercially, can be used as ligands for the Pd catalysts. Despite their lower basicity compared to tertiary monophosphines, the catalyst activity is only insignificantly affected and the desired nucleophile-substituted compounds are obtained in high yields.
A first object of the invention is a process for the coupling of
a) nucleophiles selected from the group of alcohols, thioles, amines, metallised hydrocarbons, CH-acidic compounds and metal cyanides, or of
b) carbon monoxide mixed with water, alcohols, ammonia, primary or secondary amines,
to organic compounds selected from the group of leaving-group-containing aromatics, hetero-aromatics with a C-bonded leaving group, aromatic or hetero-aromatic methyl compounds with a leaving group bonded to the methyl group, ethylenically unsaturated organic compounds with a C-bonded leaving group, or organic allyl compounds with a leaving group in allyl position, or
c) vinyl compounds with leaving-group-containing aromatics,
whilst cleaving the leaving group in the presence of Pd complexes with monophospholine ligands as the catalyst, whereby variants b) and c) are carried out in the presence of an inorganic base or organic nitrogen base, the process being characterised in that the Pd complex contains secondary monophosphines with aliphatic, branched or cyclic substituents as ligands.
The monophosphines used according to the invention may correspond, for example, to formula I,
HPR1R2xe2x80x83xe2x80x83(I),
wherein R1 and R2, independently of one another, signify xcex1-branched alkyl or cycloalkyl, or R1 and R2, together with the P-atom, represent a P-heterocycloaliphatic radical with a total of 4 to 8 ring members. R1 and R2 may be substituted or unsubstituted.
R1 and R2 may be unsubstituted or substituted. Suitable substituents are, for example, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHC1-C4-Alkyl, xe2x80x94N(C1-C4-alkyl)2, xe2x80x94CN, xe2x80x94SO3H, xe2x80x94SO3M, xe2x80x94COOM, xe2x80x94COOH, xe2x80x94COOC1xe2x80x94C4-alkyl, C5-C12-cycloalkyl, C5-C12-heterocycloalkyl with 1 to 3 hetero atoms selected from the group O, S and N, C1-C4-alkoxy, C6-C12-aryl, C4-C11-heteroaryl with 1 to 3 hetero atoms selected from the group O, S and N, C7-C12-aralkyl, C5-C12-heteroaralkyl with 1 to 3 hetero atoms selected from the group O, S and N, C7-C12-aralkyl, C5-C12-heteroaralkyl with 1 to 3 hetero atoms selected from the group O, S and N, whereby M signifies Li, Na or K. Suitable substituents for the cyclic radicals are also C1-C4-alkyl. Cyclic substituents may be unsubstituted or substituted by halogen (preferably F, Cl or Br), C1-C4-alkyl C1-C4-alkoxy.
R1 and R2 as alkyl may contain for example 3 to 18, preferably 3 to 12, more preferably 3 to 8, and most preferably 3 to 6 carbon atoms. The cycloalkyl may contain for example 3 to 16, preferably 4 to 12, most preferably 5 to 10 ring carbon atoms. The P-heterocycloaliphatic radical preferably contains a total of 5 or 6 ring members.
The xcex1-branched alkyl in question may be alkyl groups whose xcex1-carbon atom is substituted by one to three alkyl radicals. The alkyl radicals preferably contain 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms and most preferably 1 or 2 carbon atoms. Examples of alkyl radicals are butyl, propyl and preferably ethyl or methyl. A few examples of branched alkyl are isopropyl, iso- and tert.-butyl, 2-methyl-but-2-yl, 2- or 3-pentyl, 2-methyl-hex-2-yl and 2-heptyl.
The cycloalkyl in question may be mono- or polycyclic ring systems. The polycyclic ring systems may consist of, for example, 2 to 4 condensed rings. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2,2,2]-bicyclooctyl, [3,2,1]-bicyclooctyl, [3,2,2]-bicyclononyl, and adamantyl.
The P-heterocycloaliphatic radical in question is preferably radicals in which R1 and R2 in formula I together are tetra- or pentamethylene.
An especially preferred group of secondary monophosphines is the one in which R1 and R2 are selected from the group isopropyl, isobutyl, tert.-butyl, cyclopentyl, cyclohexyl, norbornyl and adamantyl.
Leaving groups are known and are described in literature. Examples of leaving groups are, in particular, halides such as chloride, bromide and iodide, as well as the group Rxe2x80x94S(O2)xe2x80x94Oxe2x80x94, wherein R is fluorine, alkyl, halogen-alkyl, phenyl, halogen-phenyl, mono-, di- or trimethylphenyl or mono-, di- or tri(halogenmethyl)phenyl. Examples are fluorosulfonyloxy, methylsulfonyloxy, trifluoromethylsulfonyloxy, nonaflate and tosylate. Other known leaving groups are phosphoric acid ester groups of the formula (RO)2P(O)Oxe2x80x94. Preferred leaving groups are halides; chloride and bromide are especially preferred. The organic compound may contain one or more leaving groups, for example 1 to 4, preferably one or two leaving groups. At least 0.5 equivalents of nucleophiles are used per leaving group, for example 1 to 5 or 1 to 2 equivalents per leaving group.
The organic compounds with leaving groups that may be mentioned are first of all aromatics. They may also be hydrocarbon aromatics, which contain, for example, 6 to 18 carbon atoms, preferably 6 to 16 carbon atoms, most preferably 6 to 12 carbon atoms.
Examples of hydrocarbon aromatics are benzene, pentalene, indan, indene, indoline, naphthalene, acenaphthylene, anthracene, phenanthrene, fluorene, pyrene, chrysene, naphthacene, diphenyl, diphenylether, diphenylthioether, diphenylmethane and stilbene. Benzene, diphenyl and naphthalene are preferred.
The organic compounds with leaving groups that may be mentioned are also hetero-aromatics. The hetero-aromatics may contain, for example 3 to 16 carbon atoms, preferably 4 to 13 carbon atoms, most preferably 4 to 9 carbon atoms, and at least one hetero atom selected from the group O, S, N and P.
Examples of hetero-aromatics are thiophene, benzothiophene, furan, benzofuran, pyran, chromene, pyrrole, imidazole, pyrazole, pyridine, bipyridyl, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, carbazole, acridine, phenanthroline, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, phenoxazine, pyrazole, piccoline, and lutidine.
The hydrocarbon aromatics and hetero-aromatics may be unsubstituted or substituted by at least one inert substituent, for example 1 to 4 inert substituents. Examples of substituents are C1-C8-, preferably C1-C4-alkyl, C1-C8-, preferably C1-C4-alkoxy, C1-C8-, preferably C1-C4-halogenalkyl, C1-C8-, preferably C1-C4-hydroxyalkyl, C1-C8-, preferably C1-C4-cyanoalkyl, xe2x80x94CN, xe2x80x94NHC1-C4-alkyl, xe2x80x94N(C1-C4-alkyl)2, C1-C8-, preferably C1-C4-alkyl-NH2, C1-C8-, preferably C1-C4-alkyl-NHC1-C4-alkyl, C1-C8-, preferably C1-C4-alkyl-N(C1-C4-alkyl)2, C1-C8-, preferably C1-C4-alkyl-X with X equal to xe2x80x94COOH, xe2x80x94COOM, xe2x80x94COOxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94NH2 xe2x80x94COxe2x80x94NHxe2x80x94C1-C4aAlkyl, xe2x80x94COxe2x80x94N(C1-C4-alkyl)2; benzyl, xe2x80x94COOH, xe2x80x94COOM, xe2x80x94CHO, xe2x80x94COOxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94N(C1-C4-alkyl)2; C1-C8- and preferably C1-C4-alkyl-COxe2x80x94, C6-C10-aryl-COxe2x80x94, xe2x80x94NO2, xe2x80x94SO2xe2x80x94C1-C4-alkyl, xe2x80x94SO2xe2x80x94C1-C4-alkoxy, xe2x80x94SO3H, SO3M, xe2x80x94Sxe2x80x94C1-C4-alkyl, whereby M is an alkali metal, for example Li, Na and K.
Examples of alkyl substituents are methyl, ethyl, n- and isopropyl, n-, iso- and tert.-butyl, pentyl, hexyl and octyl. Examples of alkoxy substituents are methoxy, ethoxy, n- and isopropoxy, n-, iso- and tert.-butoxy, pentoxy, hexoxy and octoxy. Examples of halogen-alkyl substituents are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, perfluoroethyl, chloroethyl, n- and iso-chloro- or fluoropropyl, n-, iso- and tert-chlorobutyl. Examples of hydroxy-alkyl substituents are hydroxymethyl, xcex2-hydroxyethyl, n-hydroxypropyl and n-hydroxybutyl. Examples of cyanoalkyl substituents are cyanomethyl, 2-cyanoeth-1-yl and 3-cyanoprop-1-yl.
The organic compounds with leaving groups may also be aromatic or heteroaromatic methyl compounds with a leaving group bonded to the methyl group (benzylic leaving group). Hetero-aromatics are bonded to the methyl group by a ring carbon atom. Suitable aromatics and hetero-aromatics that are bonded to the methyl group have already been mentioned. The methyl group may be substituted by one or two C1-C8-alkyl, phenyl or benzyl.
The aromatic or hetero-aromatic methyl compounds may correspond, for example, to formula II,
Raxe2x80x94CRbRcxe2x80x94Axe2x80x83xe2x80x83(II),
wherein
A is a leaving group, Ra signifies unsubstituted or substituted aryl or heteroaryl, and Rb and Rc, independently of one another, signify hydrogen, C1-C8-alkyl, phenyl or benzyl, which are unsubstituted or substituted by C1-C4-alkyl, C1-C4-alkoxy, NHC1-C4-alkyl, xe2x80x94N(C1-C4-alkyl)2, xe2x80x94CN, xe2x80x94SO3H, xe2x80x94SO3xe2x80x94C1-C4-alkyl, xe2x80x94SO3M, xe2x80x94COOM, xe2x80x94COOH, xe2x80x94COOC1-C4-alkyl, xe2x80x94COONH2, xe2x80x94COONHC1-C4-alkyl2, xe2x80x94COON(C1-C4-alkyl)2, C5-C12-cycloalkyl, C5-C12-hetero-cycloalkyl with 1 to 3 hetero atoms selected from the group O, S and N, C1-C4-alkoxy, C6-C12-aryl, C4-C11-heteroaryl with 1 to 3 hetero atoms selected from the group O, S and N, C7-C2-aralkyl, C5-C12-heteroaralkyl with 1 to 3 hetero atoms selected from the group O, S and N, whereby M signifies Li, Na or K. Cyclic substituents may be unsubstituted or substituted by halogen (preferably F), C1-C4-alkyl C1-C4-alkoxy.
In the compounds of formula II, Rc is preferably H and R is preferably hydrogen, or unsubstituted or substituted C1-C6-alkyl, phenyl or benzyl.
The organic compounds with leaving groups may also be ethylenically unsaturated organic compounds, in which the leaving group is bonded to a vinylic carbon atom. The compounds may be open-chained or cyclic and contain for example 2 to 30, preferably 2 to 20 carbon atoms and optionally hetero atoms selected from the group O, S and N. The compounds may be unsubstituted or may be substituted as defined above for Rb. Preferably at least one hydrogen atom is bonded to the carbon atoms of the ethylenically unsaturated group. More preferably, one hydrogen atom is bonded to each carbon atom of the ethylenically unsaturated group. The compounds may correspond, for example, to formula III,
RdReCxe2x95x90CRfxe2x80x94Axe2x80x83xe2x80x83(III),
wherein
A is a leaving group,
Rd and Re, independently of one another, are hydrogen or an open-chained or cyclic hydrocarbon radical or hetero-hydrocarbon radical with hetero atoms, selected from the group O, S and N, which contain 1 to 30, preferably 1 to 20 carbon atoms.
Rf independently has the same significance as Rd and Re; at least one of Rd, Re and Rf signifies a hydrogen atom,
Rd and Re, together with the carbon atom to which they are bonded, form a hydrocarbon ring or hetero-hydrocarbon ring with hetero atoms selected from the group O, S and N, with 3 to 12 ring members;
Rd and Rf, together with the Cxe2x95x90C-group, form a hydrocarbon ring or hetero-hydrocarbon ring with hetero atoms selected from the group O, S and N, with 3 to 12 ring members;
and Rd, Re, Rf and Rg are unsubstituted or substituted by C1-C6-alkyl, C1-C6-alkoxy, C4-C7-cycloalkyl, C6-C10-aryl, C7-C12-aralkyl, C1-C4-alkyl-C6-C10-aryl, C1-C4-alkoxy-C6-C10-aryl, C1-C4-alkyl-C7-C12-aralkyl, C1-C4-alkoxy-C7-C12-aralkyl, xe2x80x94COxe2x80x94OR5, xe2x80x94COxe2x80x94NR6R7 or xe2x80x94NR6R7, wherein R5 is H, an alkali metal, C1-C6-alkyl, C4-C7-cycloalkyl, phenyl or benzyl, and R6 and R7, independently of one another, are hydrogen, C1-C6-alkyl, C4-C7-cycloalkyl, phenyl or benzyl, or R6 and R7 together signify tetramethylene, pentamethylene or 3-oxapentylene.
Examples and preferences of substituents have already been mentioned. Rd is preferably a hydrogen atom. Most preferably, Rd and Rf are each a hydrogen atom.
The radicals Rd, Re and Rf may be for example C1-C20-alkyl, and preferably C1-C12-alkyl, C1-C20-heteroalkyl and preferably C1-C12-heteroalkyl with hetero atoms selected from the group O, S and N, C3-C12-cycloalkyl and preferably C4-C8-cycloalkyl, C-bonded C3-C11-heterocycloalkyl and preferably C4-C8-heterocycloalkyl with hetero atoms selected from the group O, S and N, C3-C12-cycloalkyl-C1-C6-alkyl and preferably C4-C8-cycloalkyl-C1-C6-alkyl, C3-C11-heterocycloalkyl-C1-C6-alkyl and preferably C4-C8-heterocycloalkyl-C1-C6-alkyl with hetero atoms selected from the group O, S and N, C6-C14-aryl and preferably C6-C10-aryl, C5-C13-heteroaryl and preferably C5-C9-heteroaryl with hetero atoms selected from the group O, S and N, C7-C15-aralkyl and preferably C7-C11-aralkyl, C6-C12-hetero-aralkyl and preferably C6-C10-heteroaralkyl with hetero atoms selected from the group O, S and N.
If Rd and Re, together with the carbon atom to which they are bonded, or Rd and Rf each together with the Cxe2x95x90C-group, form a hydrocarbon ring or hetero-hydrocarbon ring, then the ring preferably contains 4 to 8 ring members. The hetero-hydrocarbon ring may contain for example 1 to 3, preferably one or two hetero atoms.
The organic compounds with leaving groups may also be organic allyl compounds with a leaving group in allyl position. The compounds may be open-chained or cyclic and contain for example 2 to 30, preferably 2 to 20 carbon atoms and optionally hetero atoms selected from the group O, S and N. The compounds may be unsubstituted or may be substituted as defined above for Rb. The compounds may correspond, for example, to formula IV,
RdReCxe2x95x90CRfCHRgxe2x80x94Axe2x80x83xe2x80x83(IV),
wherein
A is a leaving group;
Rd and Re, independently of one another, are hydrogen or an open-chained or cyclic hydrocarbon radical or hetero-hydrocarbon radical with hetero atoms, selected from the group O, S and N, which contain 1 to 30, preferably 1 to 20 carbon atoms.
Rf independently has the same significance as Rd and Re; at least one of Rd, Re and Rf signifies a hydrogen atom;
Rg has the significances of Rd;
Rd and Re, together with the carbon atom to which they are bonded, form a hydrocarbon ring or hetero-hydrocarbon ring with hetero atoms selected from the group O, S and N, with 3 to 12 ring members;
Rd and Rf, together with the Cxe2x95x90C-group, form a hydrocarbon ring or hetero-hydrocarbon ring with hetero atoms selected from the group O, S and N, with 3 to 12 ring members;
Rd and Rg, together with the Cxe2x95x90Cxe2x80x94CH-group, form a hydrocarbon ring or hetero-hydrocarbon ring with hetero atoms selected from the group O, S and N, with 4 to 12 ring members;
and Rd, Re, Rf and Rg are unsubstituted or substituted by C1-C6-alkyl, C1-C6-alkoxy, C4-C7-cycloalkyl, C6-C10-aryl, C7-C12-aralkyl, C1-C4-alkyl-C6-C10-aryl, C1-C4-alkoxy-C6-C10-aryl, C1-C4-alkyl-C7-C12-aralkyl, C1-C4-alkoxy-C7-C12-aralkyl, xe2x80x94COxe2x80x94OR5, xe2x80x94COxe2x80x94NR6R7 or xe2x80x94NR6R7, wherein R5 is H, an alkali metal, C1-C6-alkyl, C4-C7-cycloalkyl, phenyl or benzyl, and R6 and R7, independently of one another, are hydrogen, C1-C6-alkyl, C4-C7-cycloalkyl, phenyl or benzyl, or R6 and R7 together signify tetramethylene, pentamethylene or 3-oxapentylene.
Examples and preferences of substituents have already been mentioned.
The radicals Rd, Re, Rf and Rg may be for example C1-C20-alkyl, and preferably C1-C12-alkyl, C1-C20-heteroalkyl and preferably C1-C12-heteroalkyl with hetero atoms selected from the group O, S and N, C3-C12-cycloalkyl and preferably C4-C8-cycloalkyl, C-bonded C3-C11-heterocycloalkyl and preferably C4-C8-heterocycloalkyl with hetero atoms selected from the group O, S and N, C3-C12-cycloalkyl-C1-C6-alkyl and preferably C4-C8-cycloalkyl-C1-C6-alkyl, C3-C11-heterocycloalkyl-C1-C6-alkyl and preferably C4-C8-heterocycloalkyl-C1-C6-alkyl with hetero atoms selected from the group O, S and N, C6-C14-aryl and preferably C6-C10-aryl, C5-C13-heteroaryl and preferably C5-C9-heteroaryl with hetero atoms selected from the group O, S and N, C7-C15-aralkyl and preferably C7-C11-aralkyl, C6-C12-hetero-aralkyl and preferably C6-C10-heteroaralkyl with hetero atoms selected from the group O, S and N.
If Rd and Re with the carbon atom, or Rd and Rf together with the Cxe2x95x90C-group, or Rd and Rg together with the Cxe2x95x90Cxe2x80x94CH-group, form a hydrocarbon ring or hetero-hydrocarbon ring, then the ring preferably contains 4 to 8 ring members. The hetero-hydrocarbon ring may contain for example 1 to 3, preferably one or two hetero atoms.
Variant a)
The nucleophiles in question are, for example, alcohols and thioles. These may be alipharic, cycloaliphatic or aromatic alcohols and thioles, which contain 1 to 20, preferably 1 to 12, most preferably 1 to 6 carbon atoms, and are unsubstituted or substituted by C1-C4-halogenalkyl, xe2x80x94N(C1-C4-alkyl)2, xe2x80x94CN, xe2x80x94SO3H, xe2x80x94SO3M, xe2x80x94COOM, xe2x80x94COOH, xe2x80x94COOC1-C4-alkyl, C5-C12-cycloalkyl, C6-C12-heterocycloalkyl with 1 to 3 hetero atoms selected from the group O, S and N, C1-C4-alkoxy, C6-C12-aryl, C4-C11-heteroaryl with 1 to 3 hetero atoms selected from the group O, S and N, C7-C12-aralkyl, C5-C12-heteroaralkyl with 1 to 3 hetero atoms selected from the group O, S and N, whereby M signifies Li, Na or K. Suitable substituents for the cyclic radicals are also C1-C4-alkyl. Cyclic substituents may be unsubstituted or substituted by halogen (preferably F), C1-C4-alkyl, C1-C4-halogenalkyl or C1-C4-alkoxy.
Tertiary and aromatic alcohols are preferred.
The nucleophiles in question are, for example, primary and secondary amines. These may be aliphatic, cycloaliphatic or aromatic amines. The secondary amines may be N-heterocycloaliphatic amines. The amines preferably contain 1 to 30, more preferably 1 to 20, most preferably 1 to 12 carbon atoms. The amines may be unsubstituted or substituted by the substituents already defined for alcohols.
The alcohols, thioles and amines may correspond to formula II
R3xe2x80x94XHxe2x80x83xe2x80x83(V),
wherein X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94Nxe2x80x94R4, R4 is H or independently has the same significance as R3, R3 signifies a monovalent, saturated or unsaturated aliphatic radical with 1 to 12 carbon atoms, a saturated or unsaturated cycloaliphatic radical with 3 to 8 carbon atoms, a saturated or unsaturated heterocycloaliphatic radical with 3 to 8 ring members and one or two hetero atoms from the group O, S, N and NRxe2x80x2, a saturated or unsaturated cycloaliphatic-aliphatic radical with 4 to 12 carbon atoms, a saturated or unsaturated heterocycloaliphatic-aliphatic radical with 3 to 12 carbon atoms and one or two hetero atoms from the group O, S, N and NRxe2x80x2, an aromatic radical with 6 to 10 carbon atoms, a hetero-aromatic radical with 4 to 9 carbon atoms and one or two hetero atoms from the group O, S and N, an aromatic-aliphatic radical with 7 to 12 carbon atoms or a hetero-aromatic-aliphatic radical with 5 to 11 carbon atoms and one or two hetero atoms from the group O, S and N, whereby Rxe2x80x2 is C1-C8-alkyl, preferably C1-C4-alkyl, C5- or C6-cycloalkyl, C6-C10-aryl such as phenyl or naphthyl, or phenyl or phenylethyl.
or R3 and R4, together with the N-atom, form a 3- to 8-membered heterocyclic ring,
and R3 and R4 are unsubstituted or substituted by one or more identical or different radicals selected from the group C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkoxy, C1-C4-halogenalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxymethyl or -ethyl, C1-C4-halogenalkoxy, C4-C7-cycloalkyl, C4-C7-cycloalkyloxy, C4-C7-cycloalkylmethyl, C4-C7-cycloalkylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyl, phenylethyloxy, halogen, xe2x80x94OR5, xe2x80x94OC(O)R5, xe2x80x94NR5R6, xe2x80x94NHxe2x80x94C(O)xe2x80x94R5, xe2x80x94NR5xe2x80x94C(O)xe2x80x94R6, xe2x80x94CO2R5, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2xe2x80x94NHR5, xe2x80x94CO2xe2x80x94NR5R3, wherein R5 and R6, independently of one another, are C1-C4-alkyl, C4-C7-cycloalkyl, C4-C7-cycloalkylmethyl, phenyl or benzyl.
Preferred substituents are methyl, ethyl, n- and isopropyl, n- and tert.-butyl, vinyl, allyl, methyloxy, ethyloxy, n- and isopropyloxy, n-and tert.-butyloxy, trifluoromethyl, xcex2-hydroxyethyl, methoxy- or ethoxymethyl or -ethyl, trifluoromethoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyloxy, phenylethyl, halogen, xe2x80x94OH, xe2x80x94OR5, xe2x80x94OC(O)R5, xe2x80x94NH2, xe2x80x94NHR5, xe2x80x94NR5R6, xe2x80x94NHxe2x80x94C(O)xe2x80x94R5, xe2x80x94NR5xe2x80x94C(O)xe2x80x94R5, xe2x80x94CO2R5, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2xe2x80x94NHR5, xe2x80x94CO2xe2x80x94NR5R6, wherein R5 and R6, independently of one another, are C1-C4-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The aliphatic radical is preferably alkyl which may be linear or branched and contains preferably 1 to 8, more preferably 1 to 4 carbon atoms, or preferably alkenyl or alkinyl which may be linear or branched and preferably contain 2 to 8, more preferably 2 to 4 carbon atoms. If R2 and R3 are alkenyl or alkinyl, the unsaturated bond is preferably in xcex2-position to the O-atom. Examples are methyl, ethyl, n- and isopropyl, n-, iso- and tert.-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, vinyl, allyl, ethinyl and propargyl. One preferred group of aliphatic radicals is methyl, ethyl, n- and isopropyl, n-, iso- and tert.-butyl.
The cycloaliphatic radical is preferably cycloalkyl or cycloalkenyl with preferably 3 to 8, more preferable 5 or 6 ring carbon atoms. A few examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, as well as cyclopentenyl, cyclohexenyl and cyclohexadienyl. Cyclopentyl and cyclohexyl are preferred in particular.
The heterocycloaliphatic radical is preferably heterocycloalkyl or heterocycloalkenyl with preferably 3 to 6 carbon atoms, 4 to 7 ring members and hetero atoms selected from the group xe2x80x94Oxe2x80x94 and xe2x80x94NRxe2x80x2xe2x80x94, wherein Rxe2x80x2 is C1-C8-alkyl, preferably C1-C4-alkyl, C5 or C6-cycloalkyl, C6-C10-aryl, for example phenyl or naphthyl, phenyl or phenylethyl. A few examples are pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl and piperanzinyl.
The cycloaliphatic-aliphatic radical is preferably cycloalkyl-alkyl or -alkenyl with preferably 3 to 8, more preferably 5 or 6 ring carbon atoms and preferably 1 to 4, or 3 to 4, more preferably 1 or 2, or 3 carbon atoms in the alkyl group or alkenyl group. Examples are cyclopentyl- or cyclohexylmethyl or -ethyl and cyclopentyl- or cyclohexyl-propenyl.
The heterocycloaliphatic-aliphatic radical is preferably heterocycloalkyl-alkyl or -alkenyl with preferably 3 to 6 carbon atoms, 4 to 7 ring members and hetero atoms selected from the group xe2x80x94Oxe2x80x94 and xe2x80x94NRxe2x80x94, wherein R is C1-C8-alkyl, preferably C1-C4-alkyl, C5- or C6-cycloalkyl, C6-C10-aryl, for example phenyl or naphthyl, phenyl or phenylethyl, and preferably 1 to 4, more preferably 1 or 2 carbon atoms in the alkyl group, or 3 to 4, and most preferably 3 carbon atoms in the alkenyl group. Examples are pyrrolidinylmethyl or -ethyl or -propyl, pyrrolinylmethyl or -ethyl or -propyl, tetrahydrofuranylmethyl or -ethyl or -propyl, dihydrofuranylmethyl or -ethyl or -propyl, and piperanzinylmethyl or -ethyl or -propyl.
The aromatic radicals are especially naphthyl, and in particular phenyl.
The aromatic-aliphatic radicals are preferably phenyl- or naphthyl-C1-C4-alkyl or -C2-C4-alkenyl. A few examples are benzyl, naphthylmethyl, xcex2-phenylethyl and xcex2-phenylethenyl.
The heteroaromatic radicals are preferably 5- or 6-membered, optionally condensed ring systems. A few examples are pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, benzofuranyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl.
The heteroaromatic-aliphatic radicals are preferably 5- or 6-membered, optionally condensed ring systems, which are bonded by one of their carbon atoms to the free bond of an alkyl group or alkenyl group, whereby the alkyl group contains preferably 1 to 4, more preferably 1 or 2 carbon atoms, and the alkenyl group contains preferably 3 to 4, more preferably 3 carbon atoms. A few examples are pyridinylmethyl or -ethyl or -propenyl, pyrimidinylmethyl or -ethyl or -propenyl, pyrrolylmethyl or -ethyl or -propenyl, furanylmethyl or -ethyl or -propenyl, imidazolylmethyl or -ethyl or -propenyl, indolylmethyl or -ethyl or -propenyl.
R3 and R4, together with the N-atom, preferably form a 4- to 8-membered heterocyclic ring, The ring may be ethylenically unsaturated. The ring may be monocyclic rings or polycyclic bridged and/or condensed ring systems, which contain for example 2 to 4 or 2 to 3 rings. A few examples are pyrrolidine, pyrroline, morpholine, indole and piperazine.
Preferred nucleophiles from the group of alcohols and amines are alkanols with 1 to 12 carbon atoms, primary alkylamines with 1 to 12 carbon atoms, and secondary amines with 2 to 16 carbon atoms.
The alcohols and amines may also be used in the form of their alkali metal alcoholates or alkali metal amides, with potassium, sodium and lithium amides and alcoholates being preferred in particular.
Nucleophiles from the group of metallised hydrocarbons and metal cyanides are generally known. The metals may be selected from the group of alkali metals and alkaline earth metals, boron, aluminium, silicon, tin, zinc, manganese and copper. Examples of alkali metals and alkaline earth metals are Li, Na, K, Mg and Ca. Preferred alkali metals and alkaline earth metals are Li, Na, K and Mg.
The metallised cyanides are preferably alkali metal cyanides, copper(I) and zinc dicyanide. Of the alkali metal cyanides, potassium, sodium and lithium cyanides are preferred.
The metallised hydrocarbons are the generally known Grignard compounds, as well as zinc-, copper-, tin-, manganese-, silicon- and boron-organic compounds, which have been described in literature many times. Only hydrocarbon radicals may be bonded to di- to tetravalent metals, or hydrocarbon radicals and halides, hydroxide or also alkoxides. More preferably, the poly-valent metals are hydrocarbon-metal halides, whereby halogen is preferably chlorine, bromine or iodine, as well as hydrocarbon-metal hydroxides or alkoxides with preferably 1 to 6 carbon atoms in the alkoxy group.
The metallised hydrocarbons may correspond, for example, to formula VI,
R7xe2x80x94Yxe2x80x83xe2x80x83(VI),
wherein
R7 signifies a monovalent, saturated or unsaturated aliphatic radical with 1 to 12 carbon atoms, a saturated or unsaturated cycloaliphatic radical with 3 to 8 carbon atoms, a saturated or unsaturated heterocycloaliphatic radical with 3 to 8 ring members and one or two hetero atoms from the group O, S, N and NR, a saturated or unsaturated cycloaliphatic-aliphatic radical with 4 to 12 carbon atoms, a saturated or unsaturated heterocycloaliphatic-aliphatic radical with 3 to 12 carbon atoms and one or two hetero atoms from the group O, S, N and NR, an aromatic radical with 6 to 10 carbon atoms, a hetero-aromatic radical with 4 to 9 carbon atoms and one or two hetero atoms from the group O, S and N, an aromatic-aliphatic radical with 7 to 12 carbon atoms or a hetero-aromatic-aliphatic radical with 5 to 11 carbon atoms and one or two hetero atoms from the group O, S and N, whereby Rxe2x80x2 is C1-C8-alkyl, preferably C1-C4-alkyl, C5- or C6-cycloalkyl, C6-C10-aryl such as phenyl or naphthyl, or phenyl or phenylethyl.
R7 are unsubstituted or substituted by one or more, identical or different radicals selected from the group C1-C4-alkyl, C1-C4-Alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C4-C7-cycloalkyl, C4-C7-cycloalkyloxy, C4-C7-cycloalkylmethyl, C4-C7cycloalkylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyl, phenylethyloxy, halogen, xe2x80x94OR5, xe2x80x94OC(O)R5, xe2x80x94NR5R6, xe2x80x94NHxe2x80x94C(O)xe2x80x94R5, xe2x80x94NR5xe2x80x94C(O)xe2x80x94R6, xe2x80x94CO2R5, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2xe2x80x94NHR5, xe2x80x94CO2xe2x80x94NR5R6, wherein R5 and R6, independently of one another, are C1-C4-alkyl, C4-C7-cycloalkyl, C4-C7-cycloalkyl methyl, phenyl or benzyl,
Y is Li, Na, K, MgZ, ZnZ, CuZ, SnZ, BZ2, AlZ2, SiZ3, or R7SiZ2, and
Z signifies fluoride, chloride, bromide, iodide, xe2x80x94OH or C1-C4-alkoxide.
The heterocyclic radicals are bonded to the metal by a ring carbon atom. Y preferably signifies Li, Na, K, MgZ, ZnZ and MnZ, wherein Z is preferably chloride or bromide, or BZ2, wherein Z is preferably fluoride, xe2x80x94OH or C1-C6-alkoxide. The preferences and examples indicated above for R3 and its substituents also apply to R7. Alkenyl radicals and alkinyl radicals are bonded directly to Y.
Within the context of the invention, the CH-acidic compounds are understood to be those organic compounds in which at least one electron-attracting and mesomerising group is bonded to at least one carbon atom. Such groups are, for example, keto, thioketo, aldehyde, carboxylate, carbamide, nitrile, sulfine, sulfone, nitro, phosphonate and phosphonium groups. Preferred groups are keto, carboxylate, carbamide and nitrile groups. The CH-acidic compounds may contain for example 1 to 4, preferably 1 or 2 groups. Especially preferred CH-acidic compounds are malonic acid diesters, malonic acid diamides, malonic acid dinitrile and keto compounds, most preferably diketones and p-ketocarboxylates with 1 to 8 carbon atoms in the ester group.
The CH-acidic compounds may be, for example, saturated or unsaturated aliphatic, cycloaliphatic, heteroaliphatic and heterocycloaliphatic compounds with hetero atoms selected from the group O, S and N, which contain 2 to 30, preferably 2 to 20, most preferably 2 to 16 carbon atoms. The cycloaliphatic compounds may be mono- or polycyclic condensed and/or bridged rings, which contain 3 to 16, preferably 3 to 12, most preferably 4 to 8 ring members. Aromatics and/or heteroaromatics may be condensed onto one or more rings. The compounds may be unsubstituted or substituted by C1-C4-halogenalkyl, xe2x80x94N(C1-C4-alkyl)2, xe2x80x94SO3M, xe2x80x94COOM, xe2x80x94COOH, C5-C12-cycloalkyl, C5-C12-heterocycloalkyl with 1 to 3 hetero atoms selected from the group O, S and N, C1-C6-alkoxy, C6-C12-aryl, C4-C11-heteroaryl with 1 to 3 hetero atoms selected from the group O, S and N, C7-C12-aralkyl, C5-C12-heteroaralkyl with 1 to 3 hetero atoms selected from the group O, S and N, whereby M signifies Li, Na or K. Suitable substituents for the cyclic radicals are also C1-C4-alkyl. Cyclic substituents may be unsubstituted or substituted by halogen (preferably F), C1-C4-alkyl, C1-C4-halogenalkyl or C1-C4-alkoxy. Examples of saturated or unsaturated, aliphatic, cycloaliphatic, heteroaliphatic and heterocycloaliphatic radicals have already been mentioned.
The CH-acidic compounds within the context of the invention are also understood to be acetylene and monosubstituted acetylene. The substituents may be those defined for R7, including the preferences.
The nucleophiles used according to the invention are known compounds or compounds which may be prepared by known or analogous methods. Metallisation is achieved in known manner, by exchanging hydrogen in acidic compounds (OH, NH or acidic CH functions) for strong bases (for example alkali metal alcoholates), or by exchanging halogen for metals, or by exchanging metals. Metallisation of acidic compounds may take place separately prior to carrying out the process according to the invention, or prior to the reaction in situ. The preparation of Grignard compounds and other organometallic compounds is generally known. The preparation of metallised hydrocarbons by reacting alkylcarbonyl compounds or other CH-acidic compounds with strong bases (for example alkali metal alcoholates and alkali metal amides) is also generally known.
Variant b)
Carbon monoxide is introduced into the reaction container in general under high pressure and the reaction is carried out under high pressure. Within the context of the invention, high pressure may mean 0.01 to 10 MPa (megapascals), preferably 0.5 to 5 MPa.
Water, alcohols, ammonia and amines are generally used in eqivalent amounts, based on the leaving groups present in the aromatics. An excess may also be used, and these reactants can even simultaneously serve as solvents. It is preferable to use 1 to 10, especially 1 to 5 equivalents per leaving group.
The alcohols and amines in question may be the alcohols and amines described in variant a), including the preferences.
The alcohols and amines may correspond to formula Va,
R3xe2x80x94XaHxe2x80x83xe2x80x83(Va),
wherein Xa is xe2x80x94Oxe2x80x94 or xe2x80x94Nxe2x80x94R4, and R3 and R4 have the significances given for the compounds of formula V, including the configurations and preferences.
Especially preferred in variant b) are water, ammonia, alkanols with 1 to 12 carbon atoms, primary alkylamines with 1 to 12 carbon atoms, and secondary amines with 2 to 16 carbon atoms.
Variant c)
Suitable vinyl compounds are known in large number. They may be for example alkenes, cycloalkenes or monosubstituted or disubstituted ethylene. Vinyl compounds of formula VII are preferred,
R8HCxe2x95x90CHR9R10xe2x80x83xe2x80x83(VII),
wherein
R9 is H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C6-aminoalkyl, C1-C6-halogenalkyl, C1-C6-cyanoalkyl, -C1-C6-alkyl-X with X equal to xe2x80x94COOH, xe2x80x94COOM, xe2x80x94COOxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94N(C1-C4-alkyl)2; C3-C8-cycloalkyl, C3-C8-cycloalkoxy, C3-C8-hydroxycycloalkyl, C3-C8-aminocycloalkyl, C3-C8-cyanocycloalkyl, C3-C8-halogencycloalkyl, -C3-C8-cycloalkyl-X with X equal to xe2x80x94COOH, xe2x80x94COOM, xe2x80x94CN, xe2x80x94COOxe2x80x94C1-C14-alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94N(C1-C4-alkyl)2; C1-C6-alkyl-COxe2x80x94, C3-C8-cycloalkyl-CO; C6-C16-aryl, C6-C16-aryloxy, C6-C16-hydroxyaryl, C6-C16-aminoaryl, C6-C16-cyanoaryl, -C6-C16-aryl-X with X equal to xe2x80x94COOH, xe2x80x94CN, xe2x80x94COOM, xe2x80x94COOxe2x80x94C1-C14-alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94N(C1-C4-alkyl)2; C4-C16-heteroaryl, C4-C16-heteroaryloxy, C6-C16-hydroxyheteroaryl, C6-C16-aminoheteroaryl, C6-C16-cyanoheteroaryl, -C6-C16-heteroaryl-X with X equal to xe2x80x94COOH, xe2x80x94COOM, xe2x80x94COOxe2x80x94C1-C14-alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94N(C1-C4-alkyl)2; or xe2x80x94CN, xe2x80x94COOH, xe2x80x94COOM, xe2x80x94COOxe2x80x94C1-C14-alkyl, xe2x80x94COH, xe2x80x94CO-C1-C14-alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94COxe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94N(C1-C4-alkyl)2, C1-C4-alkyl-COOxe2x80x94, xe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94N(C1-C4-alkyl)2,
R8, independently, has the same significance as R4,
R10, independently, has the same significance as R4,
or R8 and R9 together are linear or branched, unsubstituted or substituted alkylene, and R10 has the above significances, and
M is Li, Na or K.
Alkylene may contain for example 1 to 10 carbon atoms. A few examples are methylene, ethylene, 1,2- und 1,3-propylene, 1,2-, 1,3- and 1,4-butylene, pentylene, hexylene, heptylene, octylene, nonylene and decylene.
Substituents for R8 and R9 together as alkylene may be selected, for example, from the significances for R8.
Preferred compounds of formula VII are ethylene, propylene, butene, pentene, hexene, acrylates or methacrylates with 1 to 4 carbon atoms in the ester group, acrylonitrile, crotonic acid esters with 1 to 4 carbon atoms in the ester group, vinyl ketones such as vinyl methyl ketone, vinyl ethyl ketone, vinyl-n- or -isopropyl ketone, vinyl-n- or -isobutyl ketone, allyl alcohol, acrylic acid, methacrylic acid, cyclohexene, cyclopentene, cycloheptene, cyclooctene, styrene and styrenes substituted by OH, F, Cl, CN, xe2x80x94COOH, xe2x80x94SO3H, C1-C6-alkyl, C1-C6-alkoxy; xcex1-methylstyrene and xcex1-methylstyrenes substituted by OH, F, Cl, CN, xe2x80x94COOH, xe2x80x94SO3H, C1-C6-alkyl, C1-C6-alkoxy; heteroaromatic vinyl compounds such as vinyl pyridine, vinyl pyrrolidone and vinyl pyrrole, and corresponding heteroaromatic vinyl compounds substituted by OH, F, Cl, CN, xe2x80x94COOH,xe2x80x94SO3H, C1-C6-alkyl, C1-C6-alkoxy.
In variant c), the hydrocarbon- and hetero-aromatics described for variants a) and b) may be used, including the preferences and configurations.
The vinyl aromatics produced by the process according to the invention may be described by the formula ArR8Cxe2x95x90CR9R10, wherein Ar is unsubstituted or substituted aryl or heteroaryl, and R8, R9 and R10 have the significances given above.
Process Conditions for Variants a), b) and c)
The process according to the invention is carried out in the case of variants b) and c) and may be carried out in the case of variant a) in the presence of an inorganic base or organic nitrogen base. Suitable inorganic bases are, for example alkali metal hydroxides, alcoholates, carbonates, hydrogen carbonates, oxides, phosphates, carboxylates, silicates; and alkaline earth metal hydroxides, alcoholates, carbonates, hydrogen carbonates, oxides, phosphates, carboxylates and silicates. Specific examples are LiOH, NaOH, KOH, Mg(OH)2, Ca(OH)2, Ba(OH)2, CaO, MgO, lithium, potassium and sodium tertiary butylate, lithium, potassium, sodium and cesium carbonate, lithium, sodium and potassium amides, lithium, sodium and potassium hydride. Suitable organic nitrogen bases are secondary and tertiary amines, for example diethyl-, trimethyl-, triethyl-, methyidiethyl-, tri-n-propyl, tri-n-butylamin, diethyl-iso-propylamine, as well as cyclic tertiary amines, for example 2H-pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 3H-indole, 1H-indazole, purine isoquinoline, quinoline, phthalazine, naphthydrine, quinoxaline, quinazoline, pteridine, acridine, phenanthroline, phenazine, imidazoline, triazine, 2-piccoline, lutidine, benzimidazole, methylimidazole, pyrazole, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 1,3,5-triazine and 4-methylaminopyridine.
Preference is given to Li, Na, K, Cs carbonate, hydrogen carbonate, acetate, Na and K phosphate, Na t-butylate, CaO, MgO, triethylamine and tributylamine. Particular preference is given to sodium or potassium carbonate, sodium or potassium-C1-C4-carboxylate, trimethylamine, triethylamine or tributylamine.
When using alcohols, thioles, amines and CH-acidic compounds as nucleophiles in variant a), it is expedient and advantageous to concurrently use a base, preferably carbonates, alkoxides, phosphates and amides.
Of the metallised hydrocarbons in variant a), the addition of bases is indicated particularly in the case of boron and silicon compounds, preferably fluorides, carbonates, phosphates, hydroxides and alkoxides. It may be appropriate, if necessary, to use a metal halide salt, such as zinc, magnesium, manganese, copper halides as co-catalysts. The amount of co-catalyst will then be 0.1 to 150%, based on the metallised hydrocarbon, preferably 1 to 10%.
When using acetylenes as CH-acidic compounds, it may be advantageous to add copper salts as co-catalysts, and bases, for example tertiary amines.
The process according to the invention may be carried out without or in the presence of an inert solvent. Suitable solvents are, for example aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogen-hydrocarbons (methylene chloride, chloroform, di- and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethylether, dibutylether, tert.-butylmethylether, ethylene glycol dimethylether, ethylene glycol diethylether, diethylene glycol dimethylether, tetrahydrofuran, dioxane, ketones (acetone, methyl isobutyl ketone), carboxylates and lactones (ethyl and methyl acetate, valerolactone), N-substituted lactams (N-methylpyrrolidone), carboxamides (dimethylamide, dimethylformamide), acyclic ureas (tetramethylurea) or cyclic ureas (dimethyl imidazolidinone), and sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone) and alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether) and water. The solvents may be used on their own or in a mixture of at least two solvents.
Preferred solvents are N,N-alkylated carboxamides and lactams, such as dimethylacetamide, dimethylformamide, N-methylpyrrolidone, as well as propylene carbonate, dimethylsulfoxide, dioxane, acetonitrile, toluene, xylene, dimethylimidazolidinone (DMI) and 1,2-dimethyl-3,4,5,6-tetrahydro-pyrimidinone (DMPU).
The reaction may be carried out at normal pressure or at slight excess pressure. Elevated temperature in the context of the invention can mean a temperature range of 30 to 250xc2x0 C., preferably 50 to 200xc2x0 C., most preferably 80 to 160xc2x0 C.
Pd complexes of phosphines and their preparation are known, and the complexes used according to the invention can be described by the formula Pd(secondary phosphine)2 or Pd(secondary phosphine)4. The catalytically active variants in the reaction according to the invention may deviate from these formulae.
Pd catalysts are generally obtained from Pd(II) or Pd(0) compounds by complexing with secondary monophosphines. Suitable Pd compounds are, for example, palladium dihalides and diacetate, palladium sulfate, Pd(acetyl acetonate)2, Pd2(dibenzylidene acetone)3, Pd(CH3CN)2X2, Pd(PhCN)2X2, Pd(allyl)Cl, PdO, Pd(OH)2, Pd(NO3)2, Na2PdCl4, H2PdCl4 and palladacyclic compounds of formula IX.
The catalyst may be prepared in various ways. For example, the catalyst may be produced separately, and then used as an isolated Pd complex. In the case, it may be expedient to additionally add secondary monophosphines to the reaction mixture, for example up to a ten times excess, based on the Pd-secondary monophosphine complex. The isolated catalyst may be presented, optionally in a solvent, and then the reactants and a base added, or the isolated catalyst may be added to the optionally dissolved reactants and a base, in order to start the reaction and bring it to an end by means of heating.
It is especially advantageous in the process according to the invention for the catalyst to be produced in situ, whereby a Pd(II) salt, a Pd(II) complex salt or a Pd(0) complex optionally in a solvent is presented or prepared, and then at least equimolar amounts of the secondary monophosphine or an excess (for example an equimolar excess) are added. Then, an aromatic, a nucleophile and a base, and optionally further solvent, are added to this mixture, the reaction is started by heating and is brought to an end at an elevated temperature. The procedure involved in this in situ production of the catalyst may also be as follows: an optionally heated solution of all reactants and a base is presented, and then a Pd(0) or Pd(II) compound and then the secondary monophosphine, or first the secondary monophosphine and then a Pd(0) or Pd(II) compound are added after one another. Then, the desired reaction temperature is selected and the reaction brought to an end. In a further variant for the in situ formation of the catalyst, a Pd(0) or Pd(II) compound and a secondary monophosphine with or without solvent are placed in an aromatic containing a leaving group, the mixture is conditioned with heating and then the reactants and reaction assistants are added.
As described above, the palladium catalyst can also be formed from a heterogeneous catalyst precursor, for example colloidal Pd(0), Pd(0) applied to carrier materials or Pd(II) compounds applied to carrier materials, such as PdO or Pd(II) salts. Suitable carrier materials are for example inorganic metal oxides, silicates and carbon.
The catalyst may be used in a concentration of 0.0001 mol % to 10 mol %, preferably in a concentration of 0.001 mol % to 5 mol %, most preferably 0.01 mol % to 3 mol %, based on the aromatic compound. The molar ratio of phosphine to palladium in the reaction mixture may be 1:1 to 100:1, preferably 1:1 to 10:1, more preferably 1:1 to 4:1.
The inorganic bases and organic nitrogen bases can be used in catalytic to stoichiometric amounts or in an excess, based on the aromatics. The amount may be for example 0.5 to 50, preferably 0.9 to 5, most preferably 1 to 3 equivalents, based on the aromatic compound.
Owing to the sensitivity to air of secondary monophosphines, the process is preferably carried out in an oxygen-free inert gas atmosphere. Suitable inert gases are for example nitrogen and noble gases, such as helium, neon and argon.
Another object of the invention is the use of Pd-phosphine complexes with secondary aliphatic monophosphines as catalysts for the coupling of
a) nucleophiles selected from the group alcohols, thioles, amines, metallised hydrocarbons, CH-acidic compounds and metal cyanides, or of
b) carbon monoxide mixed with water, alcohols, ammonia, primary or secondary amines, to organic compounds selected from the group of leaving-group-containing aromatics, hetero-aromatics with a C-bonded leaving group, aromatic or hetero-aromatic methyl compounds with a leaving group bonded to the methyl group, ethylenically unsaturated organic compounds with a C-bonded leaving group, or organic allyl compounds with a leaving group in allyl position, or
c) vinyl compounds with leaving-group-containing aromatics,
whilst cleaving the leaving group.
Another object of the invention is a kit of (a) an optionally dissolved Pd(II) salt, a Pd(II) complex salt or a Pd(0) complex, and (b) an optionally dissolved secondary monophosphine, which are found in separate containers. The molar ratio of phosphine to palladium may be 1:1 to 100:1, preferably 1:1 to 10:1, more preferably 1:1 to 4:1. The components may also contain an inert solvent, whereby the concentration of Pd(II) salt, Pd(II) complex salt or Pd(0) complex, or secondary monophosphine, may be 1 to 90% by weight, based on the composition containing a solvent. Suitable solvents have already been named. The kit is especially suitable for the preparation and in situ production of catalyst precursors and catalysts.
It has also been found that certain palladacyclic complexes with secondary phosphine groups as a ligand are easy to produce and isolate, and even have surprisingly high stability when in contact with air. These are predominantly crystalline compounds. They are eminently suitable as catalysts in the process according to the invention and can be handled in the air without problems and without taking precautionary measures.
A further object of the invention is therefore compounds of formula VIII, 
wherein
A signifies a bivalent aromatic hydrocarbon radical;
D represents a substituent which contains atoms coordinating with palladium, and D is bonded to radical A in ortho position to the group xe2x80x94CHR11xe2x80x94;
X2 is the anion of a monobasic inorganic acid or organic acid;
n is 0 or 1;
R11 signifies hydrogen or C1-C4-alkyl;
R12 represents a secondary monophosphine with aliphatic, branched or cyclic substituents; and
A and D, together with the group xe2x80x94CHR11xe2x80x94 and the palladium atom, form a 4- to 6-membered ring.
A as an aromatic hydrocarbon radical preferably contains 5 to 18, most preferably 6 to 12 carbon atoms. A may be for example phenylene, naphthylene or cyclopentadienylene in a ferrocene frame. A most preferably signifies 1,2-phenylene.
The monobasic anion A2 may be for example Cl, Br or I, ClO4, PF6, SbCl6, anions of C1-C8-carboxylic acids (formate, acetate, propionate and benzoate), anions of Cxe2x80x94C8-halogen-carboxylic acids (chloroacetate, fluoroacetate, trichloroacetate, trifluoroacetate), anions of C1-C8-sulfonic acids (methyl sulfonate, phenyl sulfonate, tosylate), anions of C1-C8-halogen-sulfonic acids (trifluorosulfonate). X2 is preferably Br and most preferably Cl.
If R11 signifies alkyl, it may be methyl, ethyl, n- or isopropyl or n-butyl. R11 most preferably signifies hydrogen.
R12 is preferably secondary monophosphines of formula I, including the preferences and configurations.
A and D, together with the group xe2x80x94CHR11xe2x80x94 and the palladium atom, form a 5- to 6-membered ring.
The coordinating atoms in the substituent D may be for example O, S, N and P, with O and N being preferred.
The coordinating atoms may be bonded directly to the radical A, for example as xe2x80x94OH, SH, or unsubstituted or mono- or disubstituted amino or phosphine. Suitable substituents are also hydroxy-, thio-, mono- or disubstituted amino- or phosphineomethyl or -eth-2-yl. Suitable substituents for amino and phosphino are for example C1-C8- and especially C1-C4-alkyl (such as methyl, ethyl, propyl or butyl), C4-C8- and especially C5-C6-cycloalkyl, C5-C12- and especially C6-C12-cycloalkylalkyl, C6-C14- and especially C6-C10-aryl, and C7-C18- and especially C6-C12-aralkyl. The chelating atoms preferably contain no hydrogen atoms. The groups xe2x80x94OH and xe2x80x94SH are therefore preferably substituted by aliphatic radicals, for example C1-C8- and especially C1-C4-alkyl (such as methyl, ethyl, propyl or butyl), C4-C8- and especially C5-C6-cycloalkyl, or C5-C12- and especially C6-C12-cycloalkylalkyl.
Further suitable substituents D are also azo and imino groups of formulae xe2x80x94Nxe2x95x90Nxe2x80x94R13 and xe2x80x94CH2xe2x80x94Nxe2x95x90Nxe2x80x94R13 as well as xe2x80x94(R14)CHxe2x95x90Nxe2x80x94R13, xe2x80x94Nxe2x95x90CHxe2x80x94R13 and xe2x80x94CH2xe2x80x94Nxe2x95x90CHxe2x80x94R14, wherein R13 signifies C1-C4-alkyl, phenyl, cyclohexyl or benzyl, and R14 is H, C1-C8-alkyl, C5-C6-cycloalkyl, C6-C10-aryl or C6-C12-aralkyl. Other substituents D are for example those of formula xe2x80x94NHxe2x80x94C(R14)xe2x95x90NR13, wherein R13 and R14 are defined as above, and those of formula xe2x80x94X4xe2x80x94CH2xe2x80x94X5xe2x80x94R15, wherein 4 signifies xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR16xe2x80x94, R15 is H or C1-C4-alkyl, and R16 signifies H or C1-C4-alkyl. The substituent may also correspond to formula (R14)C(O)xe2x80x94NR13xe2x80x94, wherein R13 and R14 are defined as above. The substituent may also correspond to formula CHxe2x95x90Nxe2x80x94OR13 or xe2x80x94CHxe2x95x90Nxe2x80x94N(R13)2, wherein R13is defined as above.
The substituent D may also be aliphatic heterocycles, which contain a group xe2x80x94NR13xe2x80x94 or xe2x80x94PR13xe2x80x94 in the ring in xcex1-position to the bond, whereby R13 is defined as above. The heterocycle may contain 3 to 8, preferably 4 to 6 ring atoms. A few examples are pyrrolidin-2-yl, piperazin-2-yl, oxazolidin-2-yl and morpholin-2-yl.
The substituent D may also be those of formulae 
wherein R14 is defined as above, and R17 and R18 independently have the significance of R13. Two free bonds in the formulae means that the substituent in 1,2-position is condensed to the aromatic substance A.
The compounds of formulae VIII may be obtained in known manner, by reacting compounds of formula IX, 
or its binuclear derivatives with a secondary phosphine R12, wherein A, D, R11 and R12 have the significances given for formula VIII, and X3 is the anion of a monobasic inorganic or organic acid.
The reaction is suitably carried out at temperatures of for example 0 to 250xc2x0 C. and under a protective gas atmosphere (noble gases, nitrogen). The presence of solvents is an advantage. Suitable solvents have already been named. Preferred solvents are halogenated hydrocarbons and ether. The secondary diphosphine is added in equimolar amounts or in a slight excess. Isolation and purification are undertaken in known manner. If X3 is the anion of an organic acid, halogen donors are added, preferably in excess. Suitable halogen donors are metal or onium halides, for example alkali metal halides, such as LiCl, LiBr, NaCl or NaBr.
The compounds of formula IX are known or may be produced in analogous manner. The compounds are described for example by M. Pfeffer in Recl. Trav. Chim. Pays-Bas 109, pages 567 to 576 (1990), or by J. Tsuji in Palladium Reagents and Catalysts, pages 87-96 (1996), John Wiley and Sons (New York).
The nucleophile-substituted organic compounds produced according to the invention are valuable intermediates in the preparation of pharmaceutical and pesticidal active ingredients, see for example U.S. Pat. No. 5,919,930, EP-A-0385210, U.S. Pat. No. 5,536,870 (preparation of Naproxen) and EP-A-0376516 (Nabumeton), as well as optical brighteners (EP-A-0873989, intermediate for optical brighteners) and UV absorbers (U.S. Pat. No. 5,187,303).
The following examples illustrate the invention more fully.
a) Preparation of Catalysts